Italian consensus for the classification and reporting of thyroid cytology

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1 DOI /s CONSENSUS STATEMENT Italian consensus for the classification and reporting of thyroid cytology Francesco Nardi Fulvio Basolo Anna Crescenzi Guido Fadda Andrea Frasoldati Fabio Orlandi Lucio Palombini Enrico Papini Michele Zini Alfredo Pontecorvi Paolo Vitti Received: 15 January 2014 / Accepted: 7 February 2014 Ó Italian Society of Endocrinology (SIE) 2014 Introduction Thyroid nodules are diagnosed with increasing frequency in clinical practice. The first step in the management of patients presenting with thyroid nodules is an accurate triage of those who should be referred to surgery [1 5]. In spite of the advances in ultrasound (US) imaging [6 8] and the promising results of molecular analysis [9 16], this basic step still strongly relies on cytology [3]. Among the acronyms used to indicate the sampling technique for thyroid cytology (FNA, FNAB, FNAC, FNC), fine-needle aspiration (FNA) is the most frequently adopted and it will be employed in this document. When the cytologic All authors contributed equally to this work. F. Nardi Sapienza University of Rome, Rome, Italy F. Basolo P. Vitti (&) University of Pisa, Pisa, Italy paolo.vitti@med.unipi.it A. Crescenzi E. Papini Regina Apostolorum Hospital of Albano, Rome, Italy G. Fadda A. Pontecorvi Università Cattolica Del Sacro Cuore Agostino Gemelli, University Hospital, Rome, Italy A. Frasoldati M. Zini Hospital Santa Maria Nuova IRCCS, Reggio Emilia, Italy F. Orlandi University of Turin, Turin, Italy L. Palombini University of Naples Federico II, Naples, Italy specimen is obtained without aspiration the term FNC (fine-needle cytology) may be used [2]. In the recent years, a variety of four- to six-tiered reporting schemes for thyroid cytology have been proposed by different societies and institutions, with the aim of improving the communication between cytopathologists and clinicians [17]. With the aim to standardize the diagnostic terminology in thyroid FNA, in 2007 the United States National Cancer Institute (NCI) has proposed a reporting system for thyroid cytology based on the NCI Thyroid FNA State-Of-Science Consensus Conference [18]. This system has gained wide diffusion and the atlas The Bethesda System for Reporting Thyroid Cytology (BSRTC) provided well-defined criteria with exhaustive explanatory notes [19]. Following the recommendations of the 2009 European Federation of Cytology Societies (EFCS) symposium aiming at the worldwide unification of the reporting systems for thyroid cytology [20], a working group of the Royal College of Pathologists (RCPath) updated the reporting system already in use in UK since 2007 [21] using criteria that are similar to those used in BSRTC [22]. In Italy, a 5-tiered classification, proposed in 2007 by the Italian Society for Anatomic Pathology and Cytology joint with the Italian Division of the International Academy of Pathology (SIAPEC-IAP) [2], is currently used by most institutions. In 2012 the Italian Societies of Endocrinology, i.e., the Italian Thyroid Association (AIT), the Italian Association of Clinical Endocrinologists (AME), the Italian Society of Endocrinology (SIE) and the SIAPEC-IAP appointed a working panel of experts to update the former consensus in line with the indications of the EFCS. The present document provides a reporting scheme for thyroid cytology and the suggested clinical actions. This Consensus is not meant to address in detail all the morphological

2 issues, but to provide a practical guide to thyroid cytology reporting in Italy. The classification scheme, based on a shared terminology, is aimed to effectively manage patients affected by thyroid nodular disease and to be comparable with the internationally used systems [18, 19]. Methodology In order to update the former 2007 Italian classification, the literature in English language has been reviewed from 2007 until 2013 using PubMed as the search engine with key words determined by the Committee members, in a similar way to the BSRTC [18, 19]. Thus, it is not intended as a standard of practice guideline. The methodology of the present Consensus is based upon the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system [23 25]. The GRADE system is primarily focused on recommendations for treatment, but it is suitable also for releasing graded diagnostic recommendations. According to the GRADE system the quality of evidence is categorized as high, moderate or low. High-quality evidence (level of evidence LoE symbol: ) means that further research is unlikely to change our confidence in the estimate of benefit and risk. Randomized controlled trials typically represent high-quality evidence. Moderate quality evidence means that further research is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate. Observational studies and flawed are usually considered moderate evidence quality. Low-quality evidence means that any estimate of effect is uncertain. Unsystematic clinical observations are included in this group. Whenever applicable, LoE is quoted next to each reference. The GRADE system classifies the strength of recommendations into two grades (strong or weak). Strong recommendations (terminology: we recommend ) mean that benefits clearly outweigh harms and burdens, or vice versa. Weak recommendations (terminology: we suggest ) mean that benefits are closely balanced with harms and burdens. Basically, high level evidence supports strong recommendations, while biased or low-quality evidence generates weak recommendations. However, recommendations may take into account patient preferences, local circumstances, estimated magnitude of effects, and clinical expertise. Integrating quality of evidence and clinical consideration is necessary when a recommendation is released for clinical purposes. As a consequence, the strength of a recommendation can be downgraded or upgraded. General recommendations 1. FNA provides a cytological diagnosis of thyroid lesions, while the definitive assessment of the nature of the lesion is achieved by histology [2]. The clinical action should, hence, be based on both the cytology report and the complete set of clinical and instrumental findings (RG 2. Ultrasound (US) guidance is always suggested for an accurate FNA procedure [26, 27]. US guidance is recommended in non-palpable nodules, multinodular goiters and cystic lesions with a solid component [28 30] (RG 3. We recommend to perform FNA with fine (from 23 to 27 gauge) needles [31, 32] (RG In case of repeatedly inadequate FNA samples, an US-guided core needle biopsy (CNB), performed with springactivated 20 22G needles, may be considered [33 35] (RG weak). 4. The direct smear of the aspirated material on a glass slide is currently the most diffuse and cost-effective method [31, 32]. The use of May Grünwald Giemsa and/or Papanicolaou stain on direct smears is recommended (31-RG Liquid-based cytology techniques (LBC) are reliable methods in centers with specific experience [36, 37] (RG weak). 5. Different sampling and processing techniques (such as cell block and CNB) may be used in selected cases and especially when further investigations (immunochemistry and molecular biology) are required [9, 33 35, 38] (RG 6. The reported diagnostic accuracy of FNA is higher than 90 % and the expected rate of false negative and of false positive results should be \3 % (excluding follicular adenoma) [2, 32, 39]. Periodic revision of the diagnostic adequacy and appropriate corrective actions in case of unsatisfactory results are recommended (22- RG The on-site presence of an experienced cytopathologist may increase the rate of adequacy [31, 32, 40] (RG weak). 7. The cytology report should contain a short description and, whenever possible, a conclusive cytologic diagnosis should be made. A numeric code identifying a diagnostic category of lesions that are considered as having a similar malignancy risk should be added to the cytology report [2, 21, 22] (RG 8. Request forms should contain all the relevant clinical and imaging information [2, 3, 26]. Sampling site and technique must be clearly stated. The number of submitted slides and/or of other sampled materials must be specified [31] (RG

3 Table Italian thyroid cytology classification system Code Diagnostic category Cytology reporting categories We recommend the use of five diagnostic cytology categories (Table 1), as follows: TIR 1. Non-diagnostic Expected risk of malignancy (%) TIR1 Non-diagnostic Not defined Repeat US-guided FNA after at least 1 month TIR1C TIR2 TIR3A TIR3B TIR4 Non-diagnosticcystic Non-malignant/ benign Low-risk lesion (LRIL) High-risk lesion (HRIL) Suspicious of malignancy Low (variable on the basis of clinical findings) Evaluate the clinical setting and/or repeat FNA \3 Follow-up \10 a Repeat FNA/ clinical follow-up a Surgery Surgery (consider frozen section) TIR5 Malignant [95 Surgery a Expected rate of malignancy for the TIR3 subcategories is mainly found on clinical experience and is only partially based on the evidence of the published data TIR 1 category includes inadequate and/or non-representative samples. A sample should be defined as: inadequate when biased by smearing and/or fixing and/or staining artifacts or by obscuring blood; non-representative when the number of epithelial cells collected from the nodule is insufficient for a definitive diagnosis, or the sample is not consistent with the target thyroid lesion. The cytology report should specify if the sample is inadequate or non-representative and the possible causes should be mentioned (RG A cytology sample correctly smeared, fixed and stained is defined as adequate [2, 18, 31, 39, 41]. In solid lesions, at least 6 groups of 10 well-preserved epithelial cells are required to define the sample as representative [2, 31, 32] (RG Criteria of adequacy may be influenced by the cytopathologist s experience and specific skill [32] (RG weak). A sample with significant cytologic atypia that raises the suspicion of malignancy does not require a minimum number of follicular cells to be included into a suspicious category [18, 19, 21, 22] (RG Samples obtained from a cystic lesion that are characterized by erythrocytes, cellular debris and hemosiderinladen macrophages without abundant colloid with a cellularity that does not meet the requirements for adequacy should be subclassified as TIR 1C (Cystic) [22] (RG The rate of non-diagnostic results depends upon the characteristics of the lesion, technical factors, and the operator experience. FNA is reliably carried out in highvolume centers by skilled operators [22, 27, 31]. The inadequate reports (TIR 1) should not exceed 10 % (out of cystic lesions) [1, 2] (RG TIR 1 This cytologic category is not diagnostic. FNA repetition is recommended under US guidance after at least 1 month (RG US-guided CNB may be considered in case of repeatedly non-diagnostic FNA samples (33- to 35-RG weak). TIR 1C Most cystic lesions with the above reported cytology are not malignant when lacking suspicious features at US [19, 29]. As cystic papillary thyroid carcinoma cannot be ruled out with certainty, FNA repetition is recommended in cases with clinical and/or US suspicion (RG TIR 2. Non-malignant/benign TIR 2 category accounts for % of cytology reports and includes colloid goiter, hyperplastic nodules, autoimmune (Hashimoto s) and granulomatous (de Quervain s) thyroiditis, and other less frequent non-neoplastic conditions. A minor component of Hurthle cells may be present and does not exclude the diagnosis of benign nodule. In all these conditions the requirements for adequacy and representativity need to be adhered with. The following cases may be included in the TIR 2 category even if the criteria for cellular adequacy are not completely met (RG strong): (i) (ii) abundant and homogeneous colloid aspirated from lesions identified as cysts or spongiform nodules at US; such samples are reported as: in keeping with fluid from cystic colloid nodule with too few epithelial cells for confirmation [2, 21, 22]; predominant lymphocytic component in a clinically diagnosed Hashimoto thyroiditis [2, 21, 22]; The risk of malignancy of TIR 2 lesions is expected to be \3 %[19, 22, 37, 42, 43].

4 Clinical and US follow-up Repeat FNA is recommended in case of nodule growth or structural changes, and in patients who are undergoing ablative treatments [3, 4, 6, 26, 44] (RG TIR 3. Indeterminate The majority of samples in this category are characterized by a microfollicular pattern ( follicular proliferation ) that may correspond at histology to adenomatous hyperplasia, follicular adenoma and follicular carcinoma. Some cases of follicular variant of papillary carcinoma without obvious nuclear features of papillary thyroid cancer may be included here. Indeterminate lesions have been associated with a variable risk of malignancy, ranging from 5 to 30 % [18, 19]. On the basis of architectural and cytological alterations and of the background component, two subclasses at different risk of malignancy may be distinguished: TIR 3A (low-risk lesion, LRIL) and TIR 3B (high-risk lesion, HRIL). TIR 3A is characterized by increased cellularity with numerous microfollicular structures in a background of poor colloid amount. The overall proportion of microfollicles however, is not sufficient for the diagnosis of follicular neoplasm. Degenerative and regenerative changes may be present, as sometimes observed in non-neoplastic lesions [32]. Alternatively, sparsely cellular samples containing predominantly microfollicular groups, also with oxyphilic features ( Hurthle cells ), in a background of scant colloid, can fulfill the criteria for inclusion in the TIR 3A category [19]. This category also includes partially compromised specimens (because of preparation artifacts or blood contamination), with cytologic or architectural alterations that cannot be confidently classified as benign nor otherwise categorized [21, 22]. Inclusion of these samples in the LRIL subcategory must be supported by an adequate description in the cytology report. Currently, no published data are available about both the frequency of the TIR 3A subcategory and its risk of malignancy. Efforts should be made to keep the TIR 3A frequency \10 % and its cancer risk \10 %. TIR 3B is characterized by a high cellularity in a monotonous and repetitive microfollicular/trabecular arrangement, with scant or absent colloid, that is suggestive for a follicular neoplasm (FN). Samples composed exclusively or almost exclusively of Hurthle cells ( Hurthle cell neoplasm ), are also included here and the report should mention the cell type [22]. This subcategory also includes samples characterized by nuclear alterations suggestive of papillary carcinoma, which do not permit to reliably exclude malignancy, but are too mild or focal to be included in the TIR 4 category. As for the previous subcategory, no published data are available about both the frequency and the risk of malignancy in TIR 3B subcategory. Efforts should be made to keep the TIR 3B frequency under 10 % and its cancer risk between 20 and 30 %. The subdivision of the diagnostic category TIR 3 in two subcategories TIR 3A and TIR 3B with different risk of malignancy and different clinical actions is similar to the subdivision in AUS/FLUS-FN/SFN of BSRTC and to the Thy 3 a and f of BTA-RCPath [18, 19, 21, 22]. Yet, at variance with BSRTC and BTA-RCPath, our classification includes in the subcategory TIR 3B those cases with mild/ focal nuclear atypia at expected higher risk of malignancy (Table 1). This is according with the high rate of malignancy ([25 %) reported in the AUS/FLUS category in some recently published series [45 49]. A significant proportion of these lesions would actually require surgery. The surgical or conservative management depends upon both cytologic and clinical data and requires the clinician s and cytopathologist s consultation [47, 50, 51]. The clinical assessment is critical for surgical consultation. (RG strong) Additional information may be provided by immunochemical [9, 10] and molecular markers [11 16] (RG weak). TIR 3A We suggest follow-up as the preferential option in most cases (RG weak). During the follow-up repeat FNA is recommended [18, 19, 52] (RG TIR 3B We recommend surgery as the preferential option in most cases. Frozen sections are generally not recommended (RG TIR 4. Suspicious of malignancy TIR 4 category includes samples in which a definite cytologic diagnosis of malignancy is strongly suspected, but cannot be established with full confidence [2, 18, 22]. This category encompasses samples with low cellularity and mixed cell types (normal and atypical) without clearcut malignant features. Cases showing mild atypia should not be included in this category and should be classified as TIR 3B (RG Papillary carcinoma accounts for the majority of these cases. In the absence of immunocytochemistry or other ancillary techniques some cases of medullary carcinoma and lymphoma or other malignancies may be occasionally included in this category [2, 18, 22]. TIR 4 category accounts for up to 5 % of cytological diagnoses [2]. The malignancy risk of this category is

5 expected to be % [2, 18, 22, 37, 42, 43, 53] (RG Surgery is recommended (RG Intraoperative frozen sections may be considered (RG weak). Repeat FNA may be performed in cases with poor cellularity or in those which need additional techniques for a better characterization (RG TIR 5. Malignant TIR 5 category includes cases with a definitive cytologic diagnosis of malignant neoplasm (papillary, medullary, poorly differentiated and anaplastic carcinoma, lymphoma, other non-epithelial malignancies and metastases). The cytologic report should contain a cytologic description and, when possible, the diagnosis of specific tumor type (RG This category, depending on the series, accounts for 4 8 % of the cytologic diagnoses and its risk of malignancy is over 95 % [2, 18, 42, 43, 45, 54]. Surgery is recommended. The extent of surgery should be evaluated on the basis of the cytology report and of the clinical setting (RG Lesions with a diagnosis of anaplastic carcinoma, lymphoma or metastatic tumor should be addressed to additional diagnostic procedures and possibly to therapeutic procedures other than thyroidectomy (RG Conclusion FNA is the main diagnostic test for thyroid lesions and is an effective screening procedure to select patients as candidate for either conservative or surgical management. Although a definitive diagnosis can be made only after histological examination, the aim of FNA is to reduce the rate of surgery for benign disease, without missing any malignancy. For such reasons the results of FNA should always be evaluated together with all the clinical, laboratory and imaging data. The present document is intended to provide the Italian cytopathologists and clinicians with a reliable tool for their daily clinical practice. Its main purpose is to correlate the morphological features, expressed by well-defined diagnostic categories, with an increasing risk of malignancy in order to define an appropriate clinical management of patients with thyroid nodules (Table 1). The present Table 2 Comparison of the Italian classification system for thyroid cytology with the Bethesda system and the Royal college of Pathology Guidance for reporting of thyroid cytology specimens SIAPEC- AIT2013 TIR 1 Nondiagnostic TIR 1c Nondiagnostic cystic TIR 2 Nonmalignant TIR 3A Low-risk lesion (LRIL) TIR 3B High-risk lesion (HRIL) classification of thyroid cytology is comparable with the major international reporting systems [18, 22] (Table 2). A prospective, controlled, multicenter trial with evaluation of interobserver variability will be planned to validate the clinical effectiveness of this classification. Because rapid changes in this area are expected, periodic revisions are inevitable. Conflict of interest Francesco Nardi, Fulvio Basolo, Anna Crescenzi, Guido Fadda, Andrea Frasoldati, Fabio Orlandi, Lucio Palombini, Enrico Papini, Michele Zini, Alfredo Pontecorvi and Paolo Vitti declare they have no conflict of interest. References USA Bethesda I. Non-diagnostic Cystic fluid only II. Benign III. Atypia of undetermined significance or follicular lesion u.s. AUS/FLUS IV. Follicular neoplasm or suspicious for a follicular neoplasm UK RCPath Thy1/Thy1c Non-diagnostic for cytological diagnosis Unsatisfactory, consistent with cyst Thy2/Thy2c Non-neoplastic Thy 3a Neoplasm possible atypia/ non-diagnostic Thy 3f Neoplasm possible suggesting follicular neoplasm TIR 4 Suspicious of malignancy V. Suspicious of malignancy Thy 4 Suspicious of malignancy TIR 5 Malignant VI. Malignant Thy 5 Malignant 1. Vitti P, Rago T, Elisei R et al (2008) Gestione clinica del paziente con patologia nodulare tiroidea: Consenso Italiano. L Endocrinologo 9(Suppl. 4):S1 S16 (LoE n.a.) 2. Fadda G, Basolo F, Bondi A et al (2010) Cytological classification of thyroid nodules. Proposal of the SIAPEC-IAP Italian Consensus Working Group. Pathologica 102: (LoE n.a.) 3. Gharib H, Papini E, Paschke R, AACE/AME/ETA Task Force on Thyroid Nodules et al (2010) American Association of clinical endocrinologists, Associazione Medici Endocrinologi, and European Thyroid association: Medical Guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract 33(5):1 56 (LoE n.a.)

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